6155
J. Am, Chem. SOC.1983, 105, 6755-6157
stitution-spiroannulation, when El = a leaving group, nucleophilic-promoted fragmentation can be achieved to constitute an alkylative elimination or secoalkylation sequence14from a saturated ketone.
Scheme I
Acknowledgment. We thank the National Science Foundation for their generous support of our programs. Registry No. l b , 37609-29-3; 2 (isomer l ) , 86971-86-0; 2 (isomer 2), 86971-87-1; 3 (isomer I ) , 86971-88-2; 3 (isomer2), 86971-89-3; 4, 86971-90-6; 5, 86971-91-7; 6, 86971-92-8; 7, 86971-93-9; 8, 86971-94-0; 9, 86971-95-1; 10, 87037-57-8; 11, 82517-58-6; 12, 86971-96-2; 13, 82517-59-7; 14, 86971-97-3; 15, 86971-98-4; 16, 87037-58-9. (14) Trost, B. M.; Bogdanowicz, M. J. J . A m . Chem. SOC.1972,94,4777. Trost, B. M.; Bogdanowicz, M. J.; Frazee, W. J.; Salzmann, T. N. [bid. 1978, 100, 5512.
Scheme IIn
Biomimetic Approach to Plumericin Barry M. Trost,* James M. Balkovec, and Michael K.-T. Mao
Samuel M. McElvain Laboratories of Organic Chemistry Department of Chemistry, University of Wisconsin Madison, Wisconsin 53706 Received June 6, 1983 In 1951, Little and Johnstone isolated a compound that exhibited antifungal, antibacterial, and subsequently antitumor activity.' The compound, called plumericin, has been shown to possess the structure 2 by Albers-Schonberg and Schmid.2 Closely related to plumericin is a hydrated analogue 3 known as allamandin,3 a compound also possessing high antitumor activity. These densely functionalized molecules represent substantial synthetic challenges. A strategy emerges from the possibility that may be a biosynthetic precursor of plumericin. plumeride ( 1)495
?I-g(R=H) OH
1
Z6
(a) b S + F ' h , B F , - , KOH, Me,SO, room temperature; (b) LiN(CzH5),, pentane, room temperature; (c) PhSeBr ( 1 . 5 equiv), (C,H,),N (2.0 equiv), CH,Cl,, -40 "C; ( d ) MCPBA, CH,Cl,, -78 + 0 "C then add CH,=CHOC,H,, room temperature; (e) LDA, T H F , then PhSSO,Ph, T H F , -78 "C room temperature; (f) C,H,MgBr, ether, T H F , 0 "C, then CH,CHO; (8)MCPBA, CH,CI,, -78 "C + room temperature, then CCl,, CaCO,, reflux; a
2
3
This suggestion led us to consider a conjugate additiondimination approach for the formation of the tetrahydrofuran unit which simplifies the problem to 5 (see Scheme I). The dihydropyran ring of 5 represents a cyclized form of a dialdehyde such as 6, which in turn, may derive from an oxidative cleavage of an olefin as in 7. Anticipating that the butenolide substitution of 7 can evolve from the reactivity of the enolate of a saturated lactone as in 8, a major structural simplification to the saturated ketone 9 is permitted by use of the concept of substitutive spiroannulation as embodied in eq 1. The establishment of the stereochemistry
of the five chiral centers of 4 factors to the stereochemistry of the conversion of 9 to 8 since only the a-anomer of 5 can geometrically reach to form 4. While, at first glance, the need for the carbomethoxy group at C(4) of 2 tempts us to incorporate that carbon from the start, the fact that 9 (R = H) is a well-known ( 1 ) Little, J. E.; Johnstone, D. B. Arch. Biochem. 1951, 30, 445. (2) Albers-Schonberg, G.; Schmid, G.Helu. Chim. Acta 1961, 44, 1447. (3) Kupchan, S. M.; Dessertine, A. L.; Blaylock, B. T.; Bryan, R. F. J . Org. Chem. 1974, 39, 2477. (4) Schmid, H.; Bickel, H.; Meijer, T. M. Helo. Chim. Acta, 1952, 35, 415. Halpern, 0.;Schmid, H . Ibid. 1958, 4 1 , 1105. (5) Also see: Inoue, K.; Takeda, Y.; Nishimura, H.; Inouye, H.Chem. Pharm. Bull. 1979, 27, 3115.
--f
(h) Ac,O, C,H,N, DMAP, 0 "C; (i) cat OsO,, I::.H,O
THF, H,O,
1 \:
0)NalO, (3 equiv), ether, H,O, room temperature, then add NaOAc; (k) Ac,O, DMAP, (i-C3H,),NC2H5, CH,CI,, room tcmperature, and distill crude through quartz tube a t 500 "C; (I) CC1,COCl (50 equiv), 2,6-(f-C4H9),C,H3K (5 equiv), CH,CI,, room temperature; Mg(OCH,),, CH,OH, T H F , -45 "C; (n) All new compounds have been fully characterized by spectral means, and elemental composition was determined by combustion analysis and/or high-resolution mass spectroscopy. 0 "C;
compound both in the racemic6 and optically active' form led us to gamble that, even though methodology did not exist for the carbomethoxylation of an enol ether at the start of this program, a method could be found to carbomethoxylate descarbometh(6) Available in 80%yield in 3 steps from 1,3-cyclmtadiene. Apparu, M.; Barrelle, M. Tetrahedron 1978, 34, 1541. Whitesell, J. K.; Matthews, R. S.; Wang, P. K. S.Synth. Commun. 1977, 7, 355. Crandall, J. K.; Banks, D. B.; Colyer, R. A,; Watkins, R. J.; Arrington, J . P. J . Org. Chem. 1968, 33, 423. LeBel, N . A.; Spurlock, L. A . Tetrahedron 1964, 20, 215. (7) Kuritani, H.; Takaoka, Y.; Shingu, K. J . Org. Chem. 1979, 44, 452. Note Added in Proof An additional method for resolution of the alcohol precursor has been reported: Whitesell, J. K.; Minton, M. A,; Felman, S.W. J . Org. Chem. 1983, 48, 2193.
0002-7863/83/1505-6755$01.50/00 1983 American Chemical Society
6756 J. Am. Chem. Soc., Vol. 105, No. 22, 1983 oxyplumericin (4, R = H). We wish to record the first synthesis of plumericin that totally avoids the need for any protecting groups. In addition, we developed new methodology for carbomethoxylation of enol ethers. The key features of this synthesis are (1) a substitution-spiroannulation using diphenylsulfonium cyclopropylide, (2) a y-butyrolactone elaboration via sulfenylated intermediates, (3) a facile biomimetic cyclization of a lactol hydroxyl group onto a butenolide in a conjugate addition-elimination reaction, and (4) a chemoselective procedure for carbomethoxylation of an enol ether. Scheme I1 outlines the synthesis. A M e 2 S 0 solution of 9 (R = H) condenses with cyclopropyldiphenylsulfoniumfluoroborate in the presence of powdered potassium hydroxide.* The Me2S0 solution of the reaction mixture is directly extracted with pentane. A solution of lithium diethylamide in a hexane-pentane mixture is added directly to the concentrated pentane extracts of the oxaspiropentane 10 to give the vinylcyclopropanol 11. The critical stereochemistry of plumericin is put into place by temperaturecontrolled, chemoselective electrophilically initiated ring expansion of 119 with the complex derived from mixing triethyl amine and benzeneselenenyl bromide at -40 OC to give 12 in >100:1 diastereomeric purity. I3C N M R spectroscopy permits assignment of the indicated sterochemistry since C(a) of 12 shows a signal at 6 18.2; whereas, the cyclobutanone epimer shows this signal at 6 21.8.1° The successful completion of the synthesis verifies this assignment. The conversion of 12 to 13 requires a double oxidation, a Baeyer-Villiger reaction of the cyclobutanone1IJ2and conversion to the selenoxide and e1iminati0n.I~ Chemoselective bis oxidation with 2 equiv of MCPBA at -78-0 "C produces the selenoxide and y-butyrolactone. Adding of ethyl vinyl ether at this point and allowing the temperature to rise to room temperature completes the elimination to 13-a sequence that accomplishes both oxidative changes in a single step. For elaboration of the b ~ t e n o l i d e , generation '~ of a clean solution of the magnesium enolate of the sulfenylated lactone by reaction of the bis(su1fide) 14 with ethylmagnesium bromide and quenching it with acetaldehyde to give 15 proved vastly superior to use of amide bases on the monosulfenylated 1act0ne.I~ Oxidation to the sulfoxide allowed elimination to the butenolide 16, which p r d s smoothly at 76 OC.I6 To prime the hydroxyl group of 16 for its role as a leaving group in the biomimetic cyclization, it was acetylated to give 17. Of the three double bonds of 17, we require a reagent that discriminates on the basis of steric hindrance and the nucleophilicity of the double bond since, on both counts, the double bond we wish to cleave should be the most reactive. Cis hydroxylation with a catalytic amount of osmium tetraoxide proved to be the preferred reagent for initiating the olefin cleavage sequence.17 Exposing the resultant diol 18 to sodium metaperiodate for 5 min apparently forms 19. Addition of sodium acetate to buffer the acidic solution of the periodate cleavage reaction suffices to equilibrate 19 and cyclizes the requisite diastereomer to descarbomethoxyallamandin 20, mp 195-200 "C (dec). The facility of the cyclization reaction under such extraordinarily mild conditions reinforces the suggestion that it may represent the bio(8) Trost, B. M.; Bogdanowicz, M. J. J . Am. Chem. SOC.1973,95, 5311. (9) Trost, B. M.; Mao, M. K. J . Am. Chem. SOC.,preceding communication in this issue. (10) Trost, B. M.; Scudder, P. H. J . Am. Chem. SOC.1977, 99, 7601. (11) Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. SOC.1973.95, 5321. (1 2) Use of neutral hydrogen peroxide leads to an alternative regioisomeric y-butyrolactone in which the selenium serves as a regiochemical control element. See: Trost, B. M.; Buhlmayer, P.; Mao, M. Tetrahedron Lett. 1982, 23, 1443. (13) For a review see: Reich, H . J . Acc. Chem. Res. 1979, 12, 22. (14) Trost, B. M.; Mao, M. K. Tetrahedron Letr. 1980, 21, 3523. (15) For an independent study of the use of amide bases see: Hoye, T.; Kurth, M. J . J . Org. Chem. 1980, 45, 3549. (16) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J . Am. Chem. SOC.1976, 98,4887. Trost, B. M.; Leung, K. K. Tetrahedron Lett. 1975,4197. For a review, see: Trost, B. M. Acc. Chem. Res. 1978, 11, 453; Chem. Rev. 1978, 78, 363. (17) Van Rheenan, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Leu. 1976, 1973.
Communications to the Editor synthetic pathway and may not require enzyme catalysis. In this cyclization, a small amount of the geometric isomer of the exocyclic double bond is detected in the N M R spectrum [ 6 2.08 for 20 and 2.28 for isodecarbomethoxyallamandin] . Acetylation of the lactol hydroxyl group of 20 and distillation of the crude acetate in vacuo through a hot tube as a workup effects net dehydration to (&)-descarbomethoxyplumericin 21, mp 105-7 OC. From model work with dihydropyran, carbomethoxylation'* of an enol ether was best initiated by formation of the 1:l adduct 22 (eq 2) with neat trichloroacetyl chloride (room t e m p e r a t ~ r e ) ' ~ C
a\
/
C
c 2-2
1
O CI
3
/\rC02Me \C'OMe 2-4 (2)
oco2ve
% co-i);( 23
25
which either upon heating in vacuo (60 OC, 15 mm Hg) or subjecting to Hunig's base at 0 OC in CH2C12gives 23 in 84% yield. The latter forms directly from dihydropyran by carrying out the condensation of dihydropyran and trichloroacetyl chloride in the presence of 2,6-di-tert-butylpyridine. Methanolysis of 22 (anhydrous C H 3 0 H , Na2C03) followed by haloform cleavage [(C2H5),N,C H 3 0 H , room temperature] gives the lactol ether 24. Haloform cleavage of 23 [Mg(OCH,),, C H 3 0 H , room temperature] gives the carbomethoxylated enol ether 25 in 97% yield. The ability of a substrate such as 21, which possesses a great deal of functionality including several double bonds, to participate in such a sequence appeared to be a formidable obstacle.20 Gratifyingly, application of the direct sequence from dihydropyran to 23 to descarbomethoxyplumericin chemoselectively produces the trichloro ketone 26, mp 180-181 "C. Dissolving 26 in methanol and adding a solution of magnesium methoxide in methanol at -45 "C (temperature critical) completes the carbomethoxylation sequence and simultaneously the synthesis of (&)-plumericin, mp 176-178 OC. All spectral properties agreed with those recorded for the natural product.2s21 The question of an asymmetric synthesis was briefly addressed. While a resolution method for the alcohol precursor of 9 (R = H ) has been reported using camphanyl chloride,' we examined the HPLC behavior of the 0-methylmandelate esters 27 and 28.22,23Indeed, two nearly base-line separated peaks using 9:l HOMe
MeOH
hexane-ethyl acetate on a 10 Porasil column can be observed. The shorter retention time isomer showed absorptions for the vinyl protons at 6 5.38 and 5.68; whereas, these absorptions appeared at 6 4.86 and 5.40 for the longer retention time isomer. Using Mosher's model and viewing 27 and 28 in an extended Newman projection, we assign the stereochemistry depicted in 27 to the shorter retention time diastereomer. This assignment is confirmed by cleavage to the alcohol which showed a positive rotation, in agreement with the literature. The easy availability of either enantiomer by this simple method should allow the synthesis of either enantiomer of the iridoids. (1 8) Cf. carbomethoxylation of electron-rich aromatic rings: Bailey, D. H.; Johnson, R. E.; Albertson, N. F. Org. Synth. 1971, 51, 100 and references therein. (19) Effenberger, F.; Maier, R.; Schonwalder, K.-H.; Ziegler, T. Chem. Ber. 1982, 2766. (20) Compounds 20, 21, and 26 proved to be extremely sensitive to bases of all types. On the other hand, they appear to tolerate acids somewhat better. (21) Pai, B. R.; Subramanian, P. S.; Rao, V. R. Indian J . Chem. 1970,8, 851. (22) Trost, B. M. ACS Symp. Ser. 1982, 185, 1. (23) Dale, J. A,; Mosher, H. S . J . Am. Chem. SOC.1973, 95, 512.
6757
J. Am. Chem. SOC.1983, 105, 6757-6759 KH/THF 98%
Acknowledgment. We thank the National Cancer Institute of the National Institutes of Health for their generous support of our programs. Dr. P. Buhlmayer performed some of the model studies associated with this route.
PhCH,Br
or
,
reflux
HO
m s
t-C,H,Si
73%
(CH&
DMF
Registry No. (*)-2, 87037-55-6; (*)-9, 65861-37-2; 10, 86971-73-5; (*)-ll, 86971-74-6; (*)-12, 82517-60-0; (f)-13, 87037-56-7; (f)-14, 86993-52-4; 15, 86971-75-7; 16, 86971-76-8; 17, 86971-77-9; 18, 86971-78-0; (f)-20, 86971-79-1; ( f ) - 2 0 acetate, 86971-80-4; (f)-21, 83124-70-3; 23, 83124-87-2; 24, 86971-82-6; 25, 86971-83-7; (*)-26, 86993-53-5; 27, 86971-84-8; 28, 86971-85-9; C H 3 C H 0 , 75-07-0; CC13COCI, 76-02-8; cyclopropyldiphenylsulfoniumfluoroborate, 33462-
daH
99%
Roh;M (3)
Ro
81-6; dihydropyran, 110-87-2.
TMS
?
a) R = P h C H ,
Supplementary Material Available: Structures and experimental data for 13, 17, 20,21, 26, and 2 (2 pages). Ordering information is given on any current masthead page.
b) R=t~C,H,SI(CHJ,
5 and 7 to the thermodynamically more stable isomers 6 and 8. -
1
PhCHS
Br
1
-_
co +
An Umpolung of Allyl Bis(silanes). Tandem [6.5] Annulations via a Biallyl Equivalent
- + FhCH,O
-4
1
PhCH,O
1
-,
-,-Yd
Mar
I
LPkCH,d
?
TMS
PhCH,O
6
TMS
firar 1-
e--+ PhCH,O
7
-
Barry M. Trost* and Makoto Shimizu
Samuel M . McEIvain Laboratories of Organic Chemistry Department of Chemistry, University of Wisconsin Madison. Wisconsin 53706 Received July 31, 1983
PhCh,C
8
fir
Reacting 2 equiv of freshly recrystallized NBS with 4 in T H F in the presence of propylene oxide at -78 to 0 O C indeed gave a 47% yield of 8. Believing the presence of trimethylsilyl bromide may improve the rearrangement of 5 to 6 and/or 7 to 8 led us to use bromine with the result of a slight improvement in yield to 57%. The ability of cupric bromide to serve as a brominating agent4 led us to explore the possibility that allylsilanes might also be brominated by this reagent. If an allylcopper species is involved, the regioselectivity of the bromination might be independent of the structure of the allysilane. Indeed, addition of a catalytic and ease of handling of 2,3-bis[ (trimethylsilyl)methyl]-l,3-b~- amount of cupric bromide to the bromination reaction dramatically tadiene (1)* and the ability to manipulate the intermediate 2 prior improved the yield of 8 to 82%. to creation of the reactive dibromide 3j suggested the sequence Experimentally, 1 equiv of bromine in carbon tetrachloride is outlined in eq. 2. The key to this sequence was to devise a method added to a solution of 1 equiv of the bis(silane), 10 equiv of propylene oxide, and 1 mol % cupric bromide in T H F at -78 "C TMS TMS 8r R (1 5 min). After warming to 0 "C (1 5 min) and recooling to -78 OC, an additional 1 equiv of bromine in carbon tetrachloride is added (1 5 min) and the mixture warmed to 0 OC (1 5 min). The 1 I TMS Br TMS reaction is quenched with sodium sulfite and worked up in standard ? 3 1 fashion. Table I summarizes the results. The chemoselectivity is noteworthy in that ester, ketone, amide, and tert-butyldito effect an umpolung of the allylbis(si1ane) 2 without allyl inmethylsilyl ether groupings all are compatible. Most remarkably, version. We wish to record a simple solution to this problem and the dihydro aromatic ring of entry 7 does not aromatize under its utility in forming [ 6 . 5 ] ring systems especially with respect the reaction conditions. to the use of bis(phenylsulfony1)methane in cycloalkylations. The use of such dibromides in cycloalkylation with malonic We chose the dibenzyl ether 4, which derives from the adduct esters5 showed a surprising dependence on the choice of the ester of 1 and maleic anhydride according to eq 3, as a model in which of the malonate. In all cases, to minimize or avoid the dialkylation the key was envisioned to be the rearrangement of allyl bromides product 10, the malonate was added dropwise to a mixture of NaH and the dibromide 8a in DMF. With dimethyl malonate, a
The widespread occurrence of [6.5] ring systems in natural products stimulates the development of new strategies.' A potentially very flexible approach envisions a two-stage "cycloaddition" methodology of a two and subsequently a one carbon fragment to a biallyl skeleton as outlined in eq 1. The convenience
(1) Outside the obvious natural products such as steroids, which provided much of the stimulus in this field, a few recent cases of terpenes illustrate the widespread Occurrence of such structural fragments and the need for new methodology. Stearylvelutinal: Favre-Bonvin, J.; Gluchoff-Fiasson, K.; Bernillon, J. Tetrahedron Lett. 1982, 23, 1907. Melleolide: Midland, S. L.; Izac, R. R.; Wing, R. M.; Zaki, A. I.; Mannecke, D. E.; Sims, J. Zbid. 1982, 23, 2515. Sterpuric acid: Ayer, W. A,; Saeedi-Ghomi, M. H.; van Engen, D.; Tagle, B.; Clardy, J. Tetrahedron Suppl. 1981, No. 9, 379. Alliacolide and dihydrobotrydial: Hanson, J. R. Pure Appl. Chem. 1981, 53, 1155. Broderol: Ayer, W. A,; McCaskill, R. H. Can. J. Chem. 1981, 59, 2150. Merulidial: Quack, W.; Anke, T.; Oberwinkler, F.; Giannetti, B. M.; Steglich, W. J . Antibiot. 1978, 31, 737. Calomelanolactone: Bardouille, V.; Mootoo, B. S.; Hirotsu, K.; Clardy, J. Phytochem. 1978, 17, 275. Isolactarorufin: Daniewski, W. M.; Kocor, M.; Thoren, S. Pol. J . Chem. 1978, 52, 561. (2) Trost, B. M.; Shimizu, M. J . A m . Chem. SOC.1982, 104, 4299. (3) C f Gaoni, Y.;Sadeh, S. J . Org. Chem. 1980, 45, 870. Hamon, D. P. G.; Spurr, P. R. Synthesis 1981, 878. Bellus, D.; von Bredaw, K.; Sauter, M.; Weiss, C. D. Hela Chim. Acta 1973, 56, 3004. Zahierezhy, V.-I.; Musso, H. Justus Liebigs Ann. Chem. 1973, 1777. Butler, G. B.: Ottenbride, R. M. Tetrahedron Lett. 1967. 4873.
0002-7863/83/1505-6757$01.50/0
RO,C
P PhCH,O h C H , O m c o z R CO,R
9
PhCH& p n c
~ , o ~ c
PhCH,O o PhCH,O * a
CO,R
XY
RO,ChCO,R
!? mixture of the cyclopentene 9 and the cyclopropanes 11 was (4) For example, see: Haruta, A. M.; Satoh, J. Y . Chem. Left. 1980, 473. Kojima, Y.; Usui, K.; Kawaguchi, S. Bull. Chem. SOC.Jpn. 1972,45, 3127. Cardy, D. E.; Meisters, G. J . Org. Kosower, E. M.; Cole, W. J.; Wu, G.-S.; Chem. 1963, 28, 630. Nonhebel, D. C.; Russell, J. A. Tetrahedron 1970, 26, 278 1. (5) For a recent study of this type of reaction and its problems see: Oediger, H.; Moller, F. Justis Liebigs Ann. Chem. 1976, 348.
0 1983 American Chemical Society
